Project Summary. This proposal describes a 5-year-long career development program whose goal is to prepare Dr. Marta Margeta for a role of an independent investigator. The principal guidance will be provided by the project sponsor, Dr. Lily Jan, who is an internationally recognized expert on ion channel biology and has a distinguished record of training independent scientists. The project co-sponsor, Dr. Stephen DeArmond, an expert in the pathology of neurodegenerative diseases) and members of the advisory committee will provide additional guidance. The research program will address the hypothesis that ATP-sensitive K+ (KATP) channels, which link the metabolic state of the cell to its electrical activity, play a role in the pathogenesis of Parkinson's disease (PD). Activation of KATP channels protects catecholaminergic cells in culture against rotenone- and MPP+-induced cell death. In addition, the sensitivity of substantia nigra dopaminergic neurons to certain forms of neurodegeneration depends on the KATP channel subtype they express. In this project, the role of KATP channels in dopaminergic neurodegeneration will be assessed through three Specific Aims. First, we will examine the expression pattern of KATP channel subunits in the human substantia nigra using autopsy-derived tissue from people with and without PD. Second, we will determine which forms of cell death are attenuated by KATP channel activation and which KATP channel subtype mediates the protective effect. Third, we will determine whether neurotransmitter-induced internalization of KATP channels abolishes their ability to attenuate cell death. The research training will be complemented by a formal didactic program in research ethics, genetics and advanced molecular techniques. The UCSF Pathology Department is fully committed to Dr. Margeta's career development. It provides an ideal setting for training of independent physician scientists by fostering interdisciplinary and interdepartmental collaborations and encouraging the creation of individually customized career plans. Relevance: PD is the second most common neurodegenerative disease, affecting 1-1.5 million of people in the United States. Despite recent major advances, the cause of sporadic form of PD is still unknown. The research proposed in this project will yield important insight into the pathogenesis of PD and potentially aid in development of new treatments for PD and other neurodegenerative diseases.